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1.  Mitochondrial Variations in Non-Small Cell Lung Cancer (NSCLC) Survival 
Cancer Informatics  2015;14(Suppl 1):1-9.
Mutations in the mtDNA genome have long been suspected to play an important role in cancer. Although most cancer cells harbor mtDNA mutations, the question of whether such mutations are associated with clinical prognosis of lung cancer remains unclear. We resequenced the entire mitochondrial genomes of tumor tissue from a population of 250 Korean patients with non-small cell lung cancer (NSCLC). Our analysis revealed that the haplogroup (D/D4) was associated with worse overall survival (OS) of early-stage NSCLC [adjusted hazard ratio (AHR), 1.95; 95% CI, 1.14–3.33; Ptrend = 0.03]. By comparing the mtDNA variations between NSCLC tissues and matched blood samples, we found that haplogroups M/N and/or D/D4 were hotspots for somatic mutations, suggesting a more complicated mechanism of mtDNA somatic mutations other than the commonly accepted mechanism of sequential accumulation of mtDNA mutations.
PMCID: PMC4310616  PMID: 25657573
mitochondria genome; mitochondria mutations; lung cancer survival; haplogroup; mitochondrial genome resequencing
2.  Protective Effect of Sodium Nitroprusside on the Rat Small Intestine Transplanted Mucosa 
The intestinal mucosal epithelium is extremely susceptible to even brief periods of ischemia. Mucosal barrier damage, which is associated with ischemia/reperfusion (I/R) injury and consequently bacterial translocation, remains a major obstacle for clinically successful small bowel transplantation (SBT). Previous studies have demonstrated a protective effect of nitric oxide (NO) on other transplanted organs and NO mediated intestinal protection has also been reported in vitro. The aim of this study was to evaluate the effect of sodium nitroprusside (SNP), NO donor, on graft mucosal histology and molecular markers of function after SBT in rats. We used SNP in different period of heterotopic SBT rats. The groups consisted of SBT, pre-SNP group, and post-SNP group. Interestingly, the pre-SNP graft samples exhibited less damage compared to the SBT and post-SNP samples. In addition, mucosal samples from the pre-SNP group showed higher Na+-K+-ATPase activity and higher levels of laminin expression compared to the SBT and post-SNP samples. The findings of the present study reveal that SNP given before graft ischemia/reperfusion injury has a protective effect on mucosal histology and molecular markers of function in the transplanted small intestine.
PMCID: PMC4306256  PMID: 25650248
3.  Hepatic arterial reconstruction with a short-term patency by using micro T-tube in rat liver transplantation 
Microsurgery  2012;32(3):253-254.
PMCID: PMC4284139  PMID: 22407666
hepatic artery; liver transplantation; microsurgery; surgical instruments
4.  Alternative RNA Structure-Coupled Gene Regulations in Tumorigenesis 
Alternative RNA structures (ARSs), or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions. ARS may introduce premature stop codon(s) into a transcript, and render the transcript susceptible to nonsense-mediated decay, which in turn can influence the overall gene expression level. Meanwhile, ARS can regulate the presence/absence of upstream open reading frames and microRNA targeting sites in 5'UTRs and 3'UTRs, respectively, thus affecting translational efficiencies and protein expression levels. Furthermore, since ARS may alter exon-intron structures, it can influence the biogenesis of intronic microRNAs and indirectly affect the expression of the target genes of these microRNAs. The connections between ARS and multiple regulatory mechanisms underline the importance of ARS in determining cell fate. Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis. Here I will review our current knowledge in this field, and discuss potential future directions.
PMCID: PMC4307256  PMID: 25551597
gene regulation; alternative splicing; alternative promoter usage; alternative cleavage and polyadenylation; untranslated region; nonsense-mediated decay; upstream open reading frame; internal ribosome entry site; microRNA; tumorigenesis
5.  Serum miRNA profiling identifies miR-150/30a as potential biomarker for workers with damaged nerve fibers from carbon disulfide 
Industrial Health  2014;53(1):38-47.
As crucial small regulatory molecules, serum microRNAs (miRNAs) have been widely identified as potential noninvasive biomarkers. To survey and identify serum miRNAs associated with workers who had experienced injury to their nerve system from carbon disulfide (CS2), we profiled abnormally expressed miRNAs using the microarray technique and further performed qRT-PCR validation in case and control samples (n=20). Microarray profiling in pooled RNA samples showed that many miRNAs in workers exposed to CS2 were aberrantly expressed. Based on control samples exposed to CS2, a great amount of abnormal miRNAs, including some miRNA gene clusters and families, were obtained from microarray datasets. Most of deregulated miRNAs were up-regulated, and almost all miRNAs showed consistent expression patterns between workers with different numbers of damaged nerve fibers. Functional enrichment analysis suggested that these abnormal miRNAs showed versatile roles by contributing to multiple biological processes. Some aberrantly expressed miRNAs were characterized as miRNA gene clusters or families, and they always showed consistent expression patterns. miR-150 and miR-30a were selected to be further validated by qRT-PCR as up-regulated species, and they could discern case samples from control samples. miR-150 and miR-30a may be potential noninvasive biomarkers for a damaged nervous system.
PMCID: PMC4331193
microRNA (miRNA); Carbon disulfide (CS2); Biomarker
6.  Polarization-dependent optical absorption of MoS2 for refractive index sensing 
Scientific Reports  2014;4:7523.
As a noncentrosymmetric crystal with spin-polarized band structure, MoS2 nanomaterials have attracts increasing attention in many areas such as lithium ion batteries, flexible electronic devices, photoluminescence and valleytronics. The investigation of MoS2 is mainly focused on the electronics and spintronics instead of optics, which restrict its applications as key elements of photonics. In this work, we demonstrate the first observation of the polarization-dependent optical absorption of the MoS2 thin film, which is integrated onto an optical waveguide device. With this feature, a novel optical sensor combining MoS2 thin-film and a microfluidic structure has been constituted to achieve the sensitive monitoring of refractive index. Our work indicates the MoS2 thin film as a complementary material to graphene for the optical polarizer in the visible light range, and explores a new application direction of MoS2 nanomaterials for the construction of photonic circuits.
PMCID: PMC4268638  PMID: 25516116
7.  Functional Implications of RNA Splicing for Human Long Intergenic Noncoding RNAs 
Long intergenic noncoding RNAs (lincRNAs) have been suggested as playing important roles in human gene regulation. The majority of annotated human lincRNAs include multiple exons and are alternatively spliced. However, the connections between alternative RNA splicing (AS) and the functions/regulations of lincRNAs have remained elusive. In this study, we compared the sequence evolution and biological features between single-exonic lincRNAs and multi-exonic lincRNAs (SELs and MELs, respectively) that were present only in the hominoids (hominoid-specific) or conserved in primates (primate-conserved). The MEL exons were further classified into alternatively spliced exons (ASEs) and constitutively spliced exons (CSEs) for evolutionary analyses. Our results indicate that SELs and MELs differed significantly from each other. Firstly, in hominoid-specific lincRNAs, MELs (both CSEs and ASEs) evolved slightly more rapidly than SELs, which evolved approximately at the neutral rate. In primate-conserved lincRNAs, SELs and ASEs evolved slightly more slowly than CSEs and neutral sequences. The evolutionary path of hominid-specific lincRNAs thus seemed to have diverged from that of their more ancestral counterparts. Secondly, both of the exons and transcripts of SELs were significantly longer than those of MELs, and this was probably because SEL transcripts were more resistant to RNA splicing than MELs. Thirdly, SELs were physically closer to coding genes than MELs. Fourthly, SELs were more widely expressed in human tissues than MELs. These results suggested that SELs and MELs represented two biologically distinct groups of genes. In addition, the SEL–MEL and ASE–CSE differences implied that splicing might be important for the functionality or regulations of lincRNAs in primates.
PMCID: PMC4264600  PMID: 25574121
long intergenic noncoding RNA; alternative splicing; sequence evolution; gene regulation
8.  Chelator-Free Synthesis of a Dual-Modality PET/MRI Agent 
Angewandte Chemie (International ed. in English)  2013;52(50):10.1002/anie.201306306.
PMCID: PMC3855680  PMID: 24166933
radioarsenic; SPION; PET; MRI; lymph node mapping; multimodality imaging
9.  Effect of ambroxol on the concentration of cefotaxime in the bronchoalveolar lavage fluid of rats with pulmonary fibrosis 
This study aimed to investigate the effect of ambroxol on the concentration of cefotaxime in the bronchioalveolar lavage fluid of rats with bleomycin-induced pulmonary fibrosis. A total of 54 Wistar male rats were randomly divided into three groups, namely the normal control group, model group and ambroxol group. On experimental day 0, the rats were intratracheally instilled with bleomycin (5 mg/kg body weight) or sterile saline. The rats in the ambroxol group were then treated with ambroxol (35 mg/kg/day) intraperitoneally. On days 7, 14, 28 after instillation, six rats from each group were sacrificed, bronchial alveolar fluids were recovered and the lungs were collected for histopathological examination following the injection of cefotaxime (600 mg/kg) intravenously. The concentration of cefotaxime in the bronchial alveolar fluids was assayed by a liquid chromatography-mass spectrometry method. On day 7, the concentration of cefotaxime in the bronchial alveolar fluid of the ambroxol group was lower than that of the model group. On day 14, the concentration of cefotaxime in the bronchial alveolar fluids of the ambroxol group was higher than that of the model group, and the difference between these groups was significant statistically (P<0.001). On day 28, the concentration of cefotaxime in the bronchial alveolar fluids of the ambroxol group decreased sharply, and was lower than that of the model group (P=0.126). These results indicate that ambroxol increased the concentration of cefotaxime in the bronchial alveolar fluids at the primary fibrosis stage.
PMCID: PMC4280944  PMID: 25574230
pulmonary fibrosis; ambroxol; cefotaxime
10.  Streamlined Genome Sequence Compression using Distributed Source Coding 
Cancer Informatics  2014;13(Suppl 1):123-131.
We aim at developing a streamlined genome sequence compression algorithm to support alternative miniaturized sequencing devices, which have limited communication, storage, and computation power. Existing techniques that require heavy client (encoder side) cannot be applied. To tackle this challenge, we carefully examined distributed source coding theory and developed a customized reference-based genome compression protocol to meet the low-complexity need at the client side. Based on the variation between source and reference, our protocol will pick adaptively either syndrome coding or hash coding to compress subsequences of changing code length. Our experimental results showed promising performance of the proposed method when compared with the state-of-the-art algorithm (GRS).
PMCID: PMC4256044  PMID: 25520552
genome compression; distributed source coding; graphical model
11.  Biomedical Applications of Functionalized Hollow Mesoporous Silica Nanoparticles: Focusing on Molecular Imaging 
Nanomedicine (London, England)  2013;8(12):10.2217/nnm.13.177.
Hollow mesoporous silica nanoparticles (HMSNs), with a large cavity inside each original mesoporous silica nanoparticle (MSN), have recently gained increasing interest due to their tremendous potential for cancer imaging and therapy. The last several years have witnessed a rapid development in engineering of functionalized HMSNs (i.e. f-HMSNs) with various types of inorganic functional nanocrystals integrated into the system for imaging and therapeutic applications. In this review article, we summarize the recent progress in the design and biological applications of f-HMSNs, with a special emphasis on molecular imaging. Commonly used synthetic strategies for the generation of high quality HMSNs will be discussed in detail, followed by a systematic review of engineered f-HMSNs for optical, positron emission tomography, magnetic resonance, and ultrasound imaging in preclinical studies. Lastly, we also discuss the challenges and future research directions regarding the use of f-HMSNs for cancer imaging and therapy.
PMCID: PMC3844935  PMID: 24279491
Hollow mesoporous silica nanoparticles (HMSNs); molecular imaging; nanomedicine; theranostics; cancer; optical imaging; positron emission tomography (PET)
12.  Functionalized Upconversion Nanoparticles: Versatile Nanoplatforms for Translational Research 
Current molecular medicine  2013;13(10):1613-1632.
The design, application, and translation of targeted multimodality molecular imaging probes based on nanotechnology has attracted increasing attentions during the last decade and will continue to play vital roles in cancer diagnosis and personalized medicine. With the growing awareness of drawbacks of traditional organic dyes and quantum dots, biocompatible lanthanide ion doped upconversion nanoparticles have emerged as promising candidates for clinically translatable imaging probes, owing to their unique features that are suitable for future targeted multimodal imaging in living subjects. In this review, we summarized the recent advances in the field of functionalized upconversion nanoparticles (f-UCNP) for biological imaging and therapy in vivo, and discussed the future research directions, obstacles ahead, and the potential use of f-UCNP in translational research.
PMCID: PMC3845686  PMID: 24206131
Molecular Imaging; Multimodality Probe; Personalized Therapy; Translational Research; Upconversion Nanoparticle (UCNP)
13.  Optimal Positive Cutoff Points for careHPV Testing of Clinician- and Self-Collected Specimens in Primary Cervical Cancer Screening: an Analysis from Rural China 
Journal of Clinical Microbiology  2014;52(6):1954-1961.
careHPV, a lower-cost DNA test for human papillomavirus (HPV), is being considered for cervical cancer screening in low- and middle-income countries. However, not a single large-scaled study exists to investigate the optimal positive cutoff point of careHPV test. We pooled data for 9,785 women participating in two individual studies conducted from 2007 to 2011 in rural China. Woman underwent multiple screening tests, including careHPV on clinician-collected specimens (careHPV-C) and self-collected specimens (careHPV-S), and Hybrid Capture 2 on clinician-collected specimens (HC2-C) as a reference standard. The primary endpoint was cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) (n = 127), and secondary endpoint was CIN2+ (n = 213). The area under the curves (AUCs) for HC2-C and careHPV-C were similar (0.954 versus 0.948, P = 0.166), and better than careHPV-S (0.878; P < 0.001 versus both). The optimal positive cutoff points for HC2-C, careHPV-C, and careHPV-S were 1.40, 1.74, and 0.85, respectively. At the same cutoff point, careHPV-C was not significantly less sensitive and more specific for CIN3+ than HC2-C, and careHPV-S was significantly less sensitive for CIN3+ than careHPV-C and HC2-C. Raising the cutoff point of careHPV-C from 1.0 to 2.0 could result in nonsignificantly lower sensitivity but significantly higher specificity. Similar results were observed using CIN2+ endpoint. careHPV using either clinician- or self-collected specimens performed well in detecting cervical precancer and cancer. We found that the optimal cutoff points of careHPV were 2.0 on clinician-collected specimens and 1.0 on self-collected specimens.
PMCID: PMC4042749  PMID: 24671789
14.  Homeostatic defects in B cells deficient in the E3 ubiquitin ligase ARF-BP1 are restored by enhanced expression of MYC 
Leukemia research  2013;37(12):1680-1689.
The E3 ligase ARF-BP1 governs the balance of life and death decisions by directing the degradation of p53 and enhancing the transcriptional activity of MYC. We find B cells selectively deficient in ARF-BP1 have many defects in developing and mature B cells associated with increased expression of p53 and reduced expression of Myc. Overexpression of Myc results in suppression of p53 and complete reversal of defects induced by ARF-BP1 deficiency. These findings indicate that the dynamic balance between MYC and p53 required for normal B cell maturation and function is finely tuned and critically dependent on the activities of ARF-BP1.
PMCID: PMC4077183  PMID: 24199708
ARF-BP1; MYC; p53; B cell development
15.  Lower cost strategies for triage of human papillomavirus DNA-positive women 
Using human papillomavirus (HPV) testing for cervical cancer screening in lower-resource settings (LRS) will result in a significant number of screen-positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV-positive women in LRS. This was a population-based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self-collected and two clinician-collected specimens. The self-collected and one clinician-collected specimen were tested by two HPV DNA tests—careHPV™ and Hybrid Capture 2; the other clinician-collected specimen was tested for HPV16/18/45 E6 protein. CareHPV™-positive specimens were tested for HPV16/18/45 DNA. HPV DNA-positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA-positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA-positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.
What's new?
The careHPV™ test is a novel technology for primary cervical cancer screening of women from lower-resource settings. However, triage strategies are needed to identify which HPV-positive women are at highest risk of cervical precancer and cancer. Here, multiple viable and affordable strategies to manage HPV-positive women depending on local requirements and resources are identified, based on evaluation of the performance of different triage strategies for developing countries. The different strategies for women who test positive for HPV DNA provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for cervical intraepithelial neoplasia grade 3 or cancer (CIN3+).
PMCID: PMC4232922  PMID: 24248915
HPV; triage; cervical cancer; careHPV; developing countries; E6
16.  Salivary biomarkers indicate obstructive sleep apnea patients with cardiovascular diseases 
Scientific Reports  2014;4:7046.
Although obstructive sleep apnea (OSA) patients are at high risk of developing cardiovascular disease (CVD), only a small proportion is currently diagnosed. To explore and identify the differentially expressed proteins/peptides of OSA patients with CVDs, a mass spectrometry-based salivary analysis was performed. In our study, eleven peaks were observed differentially expressed in saliva from the non-CVD and CVD groups. Five masses mass peaks (1594.1, 1673.7, 1196.6, 1290.5, and 1447.0 Da) showed an upregulated trend in the CVD group, whereas six mass peaks (3038.6, 2164.3, 2301.4, 3195.0, 2628.4, and 1721.9 Da) were downregulated in the CVD group. In addition, the alpha-2-HS-glycoprotein (AHSG) levels in saliva were verified to be decreased in CVD group compared to non-CVD group. Analysis of the salivary peptidome provides a promising approach to screening for novel biomarkers before further identification, and may contribute to early diagnosis of CVD patients with OSA.
PMCID: PMC4231342  PMID: 25395095
17.  Advances for Studying Clonal Evolution in Cancer 
Cancer letters  2013;340(2):10.1016/j.canlet.2012.12.028.
The “clonal evolution” model of cancer emerged and “evolved” amid ongoing advances in technology, especially in recent years during which next generation sequencing instruments have provided ever higher resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors. It has become increasingly clear that clonal evolution is not a single sequential process, but instead frequently involves simultaneous evolution of multiple subclones that co-exist because they are of similar fitness or are spatially separated. Co-evolution of subclones also occurs when they complement each other’s survival advantages. Recent studies have also shown that clonal evolution is highly heterogeneous: different individual tumors of the same type may undergo very different paths of clonal evolution. New methodological advancements, including deep digital sequencing of a mixed tumor population, single cell sequencing, and the development of more sophisticated computational tools, will continue to shape and reshape the models of clonal evolution. In turn, these will provide both an improved framework for the understanding of cancer progression and a guide for treatment strategies aimed at the elimination of all, rather than just some, of the cancer cells within a patient.
PMCID: PMC3783624  PMID: 23353056
18.  Acceptability and Correlates of Primary and Secondary Prevention of Cervical Cancer among Medical Students in Southwest China: Implications for Cancer Education 
PLoS ONE  2014;9(10):e110353.
To understand knowledge about, and acceptability of, cervical cancer screening and HPV vaccines among medical students; and to explore potential factors that influence their acceptability in China.
We conducted a survey among medical students at six universities across southwest China using a 58-item questionnaire regarding knowledge and perceptions of HPV, cervical cancer, and HPV vaccines.
We surveyed 1878 medical students with a mean age of 20.8 years (standard deviation: 1.3 years). Of these, 48.8% and 80.1% believed cervical cancer can be prevented by HPV vaccines and screening respectively, while 60.2% and 71.2% would like to receive or recommend HPV vaccines and screening. 35.4% thought HPV vaccines ought to be given to adolescents aged 13–18 years. 32% stated that women should start to undergo screening from the age of 25. 49.2% felt that women should receive screening every year. Concern about side effects (38.3% and 39.8%), and inadequate information (42.4% and 35.0%) were the most cited barriers to receiving or recommending HPV vaccination and cervical cancer screening. Females were more likely to accept HPV vaccines (OR, 1.86; 95% CI: 1.47–2.35) or cervical cancer screening (OR, 3.69; 95% CI: 2.88–4.74). Students with a higher level of related knowledge were much more willing to receive or recommend vaccines (P<0.001) or screening (P<0.001). Students who showed negative or uncertain attitudes towards premarital sex were less likely to accept either HPV vaccines (OR, 0.67; 95% CI: 0.47–0.96), or screening (OR, 0.68; 0.47–0.10). Non-clinical students showed lower acceptability of cervical screening compared to students in clinical medicine (OR, 0.74; 95% CI: 0.56–0.96).
The acceptability of HPV vaccines and cervical cancer screening is relatively low among medical students in southwest China. Measures should be taken to improve knowledge about cervical cancer and awareness of HPV vaccines and screening among medical students at university.
PMCID: PMC4215919  PMID: 25360743
19.  Unsupervised Spatial Event Detection in Targeted Domains with Applications to Civil Unrest Modeling 
PLoS ONE  2014;9(10):e110206.
Twitter has become a popular data source as a surrogate for monitoring and detecting events. Targeted domains such as crime, election, and social unrest require the creation of algorithms capable of detecting events pertinent to these domains. Due to the unstructured language, short-length messages, dynamics, and heterogeneity typical of Twitter data streams, it is technically difficult and labor-intensive to develop and maintain supervised learning systems. We present a novel unsupervised approach for detecting spatial events in targeted domains and illustrate this approach using one specific domain, viz. civil unrest modeling. Given a targeted domain, we propose a dynamic query expansion algorithm to iteratively expand domain-related terms, and generate a tweet homogeneous graph. An anomaly identification method is utilized to detect spatial events over this graph by jointly maximizing local modularity and spatial scan statistics. Extensive experiments conducted in 10 Latin American countries demonstrate the effectiveness of the proposed approach.
PMCID: PMC4211687  PMID: 25350136
20.  In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles 
ACS nano  2013;7(10):10.1021/nn403617j.
Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anti-cancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and 64Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that 64Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy.
PMCID: PMC3834886  PMID: 24083623
Mesoporous silica (mSiO2) nanoparticles; tumor angiogenesis; in vivo tumor targeting; positron emission tomography (PET); drug delivery; theranostics
21.  Construction and Characterization of Recombinant HSV-1 Expressing Early Growth Response-1 
ISRN virology  2014;2014:629641.
Early Growth response-1 (Egr-1) is a transcription factor that possesses a variety of biological functions. It has been shown to regulate HSV-1 gene expression and replication in different cellular environments through the recruitment of distinct cofactor complexes. Previous studies demonstrated that Egr-1 can be induced by HSV-1 infection in corneal cells but the level was lower compared to other cell types. The primary goal of this report is to generate a recombinant HSV-1 constitutively expressing Egr-1 and to investigate the regulation of viral replication in different cell types or in animals with Egr-1 overexpression. The approach utilized was to introduce Egr-1 into the BAC system containing complete HSV-1 (F) genome. To assist in the insertion of Egr-1, a gene cassette was constructed that contains the Egr-1 gene flanked byloxP sites. In this clone Egr-1 is expressed under control of CMV immediate-early promoter followed by another gene cassette expressing the enhanced green fluorescent protein (EGFP) under the control of the elongation factor 1α (EF-1 α) promoter. The constructed recombinant viruses were completed containing the Egr-1 gene within the viral genome and the expression was characterized by qRT-PCR and Western blot analyses. Our results showed that Egr-1 transcript and protein can be generated and accumulated upon infection of recombinant virus in Vero and rabbit corneal cells SIRC. This unique virus therefore is useful for studying the effects of Egr-1 during HSV-1 replication and gene regulation in epithelial cells and neurons.
PMCID: PMC4205940  PMID: 25346859
22.  A Novel Thyroid Hormone Mediated Regulation of HSV-1 Gene Expression and Replication is Specific to Neuronal Cells and Associated with Disruption of Chromatin Condensation 
Previously we showed that thyroid hormone (T3) regulated the Herpes Simplex Virus Type -1 (HSV-1) gene expression and replication through its nuclear receptor TR via histone modification and chromatin remodeling in a neuroblastoma cell line neuro-2a cells (N2a). This observation suggested that T3 regulation may be neuron-specific and have implication in HSV-1 latency and reactivation. In this study, our in vitro latency/reactivation model demonstrated that removal of T3 can de-repress the HSV-1 replication and favor reactivation. Transfection studies and infection assays indicated that HSV-1 thymidine kinase (TK), a key viral gene during reactivation, was repressed by TR/T3 in cells with neuronal origin but not in non-neuronal cells. Additional studies showed that RCC1 (Regulator of Chromosome Condensation 1) was sequestered but efficiently detected upon viral infection in N2a cells. Western blot analyses indicated that addition of T3 repressed the RCC1 expression upon infection. It is likely that diminution of RCC1 upon infection in neuronal cells under the influence of TR/T3 may lead to repression of viral replication/gene expression thus promote latency. Together these results demonstrated that TR/T3 mediated regulation is specific to neuronal cells and differential chromosome condensation may play a critical role in this process.
PMCID: PMC4205947  PMID: 25346944
HSV-1; Thyroid hormone; Chromosome; Neuron; Latency
23.  The Effects of Baclofen for the Treatment of Gastroesophageal Reflux Disease: A Meta-Analysis of Randomized Controlled Trials 
Objectives. Baclofen can relieve gastroesophageal reflux-related symptoms in healthy subjects and gastroesophageal reflux disease (GERD) patients by reducing the incidence of transient lower esophageal sphincter relaxation. This meta-analysis aimed to evaluate the efficacy and safety of baclofen for the treatment of GERD. Methods. We systematically searched randomized controlled trials published prior to November 2013 from PubMed, Medline, Embase, ScienceDirect,, and the Cochrane Central Register of Randomized Controlled Trials. We performed a meta-analysis of all eligible trials. Results. Nine studies were identified with a total of 283 GERD patients and healthy subjects. Comparative analysis provided high quality data supporting the ability of baclofen to promote a short-term decrease in the number of reflux episodes per patient, the average length of reflux episodes, and the incidence of transient lower esophageal sphincter relaxation. No serious adverse events or death events were reported, and there were no significant differences in the overall adverse events between baclofen and placebo. All reported side effects of baclofen were of mild-to-moderate intensity, and the drug was well tolerated. Conclusion. Abundant evidence suggests that baclofen may be a useful approach for the treatment of GERD patients; however, a larger well-designed research study would further confirm this recommendation.
PMCID: PMC4217339  PMID: 25389436
24.  Use of combination therapy to successfully treat breakthrough Trichosporon asahii infection in an acute leukemia patient receiving voriconazole 
Trichosporon species is an important life-threatening opportunistic systemic pathogen, especially in leukemia patients. Voriconazole is proved to be a promising agent in past decade. However, recently we observed a case of breakthrough Trichosporon asahii infection while receiving voriconazole, which calls for an alternative treatment strategy. A combination therapy of liposomal amphotericin B (AmB) plus caspofungin – in which liposomal AmB dose was reduced due to renal toxicity – was administered to successfully treat this patient.
PMCID: PMC4223824  PMID: 25383317
T. asahii; Liposomal amphotericin B; Caspofungin; Voriconazole
25.  Terpene synthases and their contribution to herbivore-induced volatile emission in western balsam poplar (Populus trichocarpa) 
BMC Plant Biology  2014;14(1):270.
As a response to caterpillar feeding, poplar releases a complex mixture of volatiles which comprises several classes of compounds. Poplar volatiles have been reported to function as signals in plant-insect interactions and intra- and inter-plant communication. Although the volatile blend is dominated by mono- and sesquiterpenes, there is much to be learned about their formation in poplar.
Here we report the terpene synthase (TPS) gene family of western balsam poplar (Populus trichocarpa) consisting of 38 members. Eleven TPS genes (PtTPS5-15) could be isolated from gypsy moth (Lymantria dispar)-damaged P. trichocarpa leaves and heterologous expression in Escherichia coli revealed TPS activity for ten of the encoded enzymes. Analysis of TPS transcript abundance in herbivore-damaged leaves and undamaged control leaves showed that seven of the genes, PtTPS6, PtTPS7, PtTPS9, PtTPS10, PtTPS12, PtTPS13 and PtTPS15, were significantly upregulated after herbivory. Gypsy moth-feeding on individual leaves of P. trichocarpa trees resulted in induced volatile emission from damaged leaves, but not from undamaged adjacent leaves. Moreover, the concentration of jasmonic acid and its isoleucine conjugates as well as PtTPS6 gene expression were exclusively increased in the damaged leaves, suggesting that no systemic induction occurred within the tree.
Our data indicate that the formation of herbivore-induced volatile terpenes in P. trichocarpa is mainly regulated by transcript accumulation of multiple TPS genes and is likely mediated by jasmonates. The specific local emission of volatiles from herbivore-damaged leaves might help herbivore enemies to find their hosts or prey in the tree canopy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0270-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4197230  PMID: 25303804
Populus trichocarpa; Sesquiterpenes; Monoterpenes; Volatiles; Terpene synthase gene family; Jasmonic acid

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